CN115103665A

CN115103665A - Phage preparation and phage application device

Info

Publication number: CN115103665A
Application number: CN202080092987.8A
Authority: CN
Inventors: 西蒙·弗兰克·荣汉斯; 贾斯特斯·格罗斯
Original assignee: Pha Technology Co ltd
Current assignee: Pha Technology Co ltd
Priority date: 2020-01-14
Filing date: 2020-11-21
Publication date: 2022-09-23
Also published as: EP4054525B1; CA3164621A1; WO2021143962A1; KR20220127896A; EP4054525A1; JP2023510889A; DE102020100725A1; US20230057086A1

Abstract

The invention relates to a phage preparation, namely an in-vivo phage preparation, a nasopharynx and pulmonary phage preparation, a skin phage preparation, a phage suture preparation, a double-syringe phage preparation, a nasopharynx and pulmonary phage preparation device and a phage sensitivity test application.

Description

Phage preparation and phage application device

The present invention relates to phage preparations (means), i.e. in vivo phage preparations, nasopharyngeal and pulmonary phage preparations, dermal phage preparations and phage suture (suture) preparations, as well as two-syringe (two-system) phage preparations, nasopharyngeal and pulmonary phage preparations devices, and phage sensitivity testing applications.

Bacteriophages, or BPH for short, are various virus groups directed against bacteria as host cells, i.e. they specifically affect the bacteria. This means that the host (e.g. a mammal, especially a human being) is not affected. Infection of bacteria or other pathogenic microorganisms by virulent bacteriophages results in a cycle of lysis of the bacteria and ultimately lysis and destruction. Endotoxin is a bacterial toxin, distinct from exotoxins, which is not secreted by living bacteria, but is released only by autolysis.

Bacteriophages have found wide application in medicine, veterinary medicine, biology, agricultural science, food processing, and especially in genetic engineering. For example, bacteriophages are used in medicine to identify bacterial pathogens because of their host specificity. The use of phages to treat bacterial infections was discovered by Felix d' Herelle, early before the discovery of penicillins and antibiotics. However, later with the introduction of chemotherapy by antibiotics, phage therapy was considered impractical and forgotten. Due to the increasing incidence of multiple antibiotic resistance, phage are now being studied again extensively as antibiotic substitutes in human medicine.

Phages may be obtained from nature. For this purpose, a water sample, blood sample, swab, human or animal secretion or other sample is collected and spread on a nutrition plate. By incubating these plates (36 ℃ -37 ℃, 24 hours), the presence of phage was found, as indicated by the lysis zone. By detecting the presence of prokaryotes, it is possible to make a preliminary judgment as to which bacteria the discovered bacteriophages have lytic activity.

For purification, plaques in bacterial lawn were cut and vortexed in snap-cap tubes (snap cap tube) containing liquid nutrient solution for at least 10 minutes. The liquid nutrient solution is removed, sterile filtered and applied to nutrient media previously inoculated with the appropriate bacteria, and incubated at 36 ℃ -37 ℃ for an additional 24 hours. Plaque was again excised and treated as described. This cycle should be repeated at least 5 times to ensure that the isolated phage present is only a clone of one phage.

To generate a larger number of phage clones of one phage, the sterile filtered phage solution from the snap-cap tube was placed on the inoculation plate after at least 5 purifications and incubated again as described. Extraction buffer was then added to the plate and stirred on the medium for 30 minutes by shaking the device. Removing the extraction buffer solution and carrying out sterile filtration to obtain a sterile phage solution.

The phage solution may be prepared by adding a stabilizer such as CaCl ₂ To stabilize and adjust the pH by using pH adjusting substances such as HCl and CH ₃ COOH、CH ₃ COO-physiological regulation to stabilize. Further preservatives may be required when the primary packaging has proven to be incapable of preventing the penetration of microorganisms, possibly in the case of non-sterile products. Preservatives, such as potassium sorbate, are used.

Antibiotic resistance is becoming a serious problem in the global healthcare sector. For decades, research efforts on fundamental new antibiotics have been inadequate, and only a few formulations have entered the market. Since then, strains have increased dramatically in order to implement new effective concepts to reduce infections caused by difficult pathogens. Politicians have recognized this need and initiated extensive subsidy planning domestically and internationally. The main content of many public subsidies is the search and development of therapeutic drugs, the effect of which is based on the minimization of new mechanisms and/or resistance development.

In the medical setting, foreign body infections are associated with complications and increased mortality; in this regard, current and future antibiotic therapy has reached a limit.

The urgent need for alternative antibiotics is the object of the present invention.

The problem arises due to the low stability of phages in vivo, since they are eliminated by phagocytes as foreign bodies in a rather short time.

The object of the present invention is to provide a technical phage delivery method and phage preparation (also known as phage library (depot)) which can be applied by means of a technical device, and a suitable application device for applying a suitable phage preparation in a spatiotemporal manner for this purpose.

Specifically, the objective is to apply the bacteriophage as an infection preventive agent in the treatment of infection to foreign bodies, homogeneous and heterogeneous tissues in different aggregation states, and a galenic composition having biological activity.

A further subsidiary object is to enable the improvement of the phages to be introduced. This secondary objective will be solved by the combined use of bacteriophages and endotoxins.

This object will be solved by a phage preparation/library according to the present invention and a phage preparation application apparatus and a phage preparation manufacturing method according to the main claim and the independent claims, respectively.

The in vivo phage preparation is formed as a sterile phage gel, wherein the gel is release-regulated; or formed into a sterile phage soft gel capsule comprising a gel; or formed as a sterile softgel chain with phage softgels including gels on monofilament (monofilamethous) hydrolytically degradable threads (threads) or non-degradable materials (e.g., when wicking is intended); or formed as a sterile phage sponge, wherein the sponge is sprayed with a phage solution or phage gel, or a phage gel prepared by freeze-drying the gel (e.g., lyophilization).

The nasopharyngeal and pulmonary phage preparations are formed as phage solutions or phage powders, wherein the above-mentioned phage preparations can be atomized using at least one of the following variants, namely by means of a respirator atomizing with a phage atomizing device, by means of a pressurized gas metered dose inhaler, by means of a jet atomizer, by means of a membrane atomizer or by means of a powder inhaler.

The skin phage preparation is formed as a sterile phage powder or as a sterile phage sponge as a wound dressing comprising a phage gel or phage powder, or as a sponge in the form of a freeze-dried phage gel.

The phage suture preparation is a monofilament suture formed in a manner of cyclic spraying with a phage solution or with a phage gel, or it is a multifilament suture wetted with a phage solution or a phage gel, the solution or gel being provided on the suture material and/or in the contact zones.

The two-syringe phage preparation is characterized in that the first syringe is prepared using a phage solution and the second syringe is prepared using a gel, wherein the two syringes can be connected to each other, in particular by means of a connector, wherein it is possible to mix the gel with the phage solution and the mixture can be used for application in a syringe. Here, the gel and the phage solution can be adjusted as necessary. In particular, different gels and/or different phage solutions can be stored for different combinations from each other and mixed with each other accordingly to form separate phage solution gels.

A nasopharyngeal and pulmonary phage formulation delivery device, wherein phage solution or phage powder can be atomized using at least one of the following devices, and the phage atomization device is formed as (at least one variant embodiment of one of the following):

-a ventilator device comprising an aerosolization device or a pressurized gas dose aerosol chamber;

-a pressurised gas metered dose inhaler;

-a container inhaler device comprising an aerosolization chamber and a jet nebulizer or a membrane nebulizer;

-an inhaler device comprising a pressurised gas metered dose inhaler;

-a powder inhaler.

Phage susceptibility testing application, characterized in that a phage, a bacterial nutrient solution and a dye are placed in a container, wherein the dye is capable of interacting with the bacterial cell wall.

The above-described embodiments of the present invention are described in further detail below:

the phage library or phage preparation or library, respectively, is a unit in which at least one phage is provided as a phage application that maintains stability for a determinable period of time after introduction into the body.

In particular, it has been recognized that bacteriophages are suitable for the treatment and prophylaxis of bacterial or inflammatory or fungal diseases, in particular because of the very low side effects associated therewith. Because of the mechanism of action, which involves the propagation of active phages only when an infection of the host by a suitable bacterium or fungus occurs, it is possible to administer prophylactically small amounts of phages and endotoxins which do not harm the host organism but propagate in a short time in the presence of the bacterium or fungus to be controlled. In general, high doses of bacteriophages are feasible in acute infections because they selectively lyse pathogenic microorganisms without harming host organisms, such as mammals.

To date, it has been speculated that the immunostimulatory effect of endotoxin may cause adverse effects on the patient's body, such as elevated temperature (fever) and many other pathophysiological effects, where the release of high doses of endotoxin may even lead to irreversible endotoxin shock. For this reason, endotoxins have hitherto been undesirable in pharmaceutical compositions (e.g. those used against bacteria). Since endotoxins are presumed to be rather harmful and at least not related to any cure success, it is presently believed that only endotoxin-free methods are suitable for use. In contrast, it has now surprisingly been found that endotoxin in combination with bacteriophage does have a positive effect on the success of the cure.

The combined use of bacteriophages and endotoxins results in a synergistic effect, in particular in wound healing. This is due to many inflammatory diseases (e.g., diabetic foot) being based on three processes, namely vascular changes, changes in nerve conduction, and infection. The use of phage may fight infection, thereby initiating the overall healing process. The additional presence of endotoxin has a positive effect on the overall healing process. This positive effect is based on the immunostimulatory properties of endotoxins.

An example of a technical implementation of phage application will be provided below. The list is based on the path of the application. The purpose of all proposed phage applications is to introduce therapeutically active phage for the prevention and/or treatment and/or minimization of bacterial infections, where not the therapeutic procedure but the product/application it is desired to focus on is the focus here. In addition, techniques related to phage production, stabilization, or testing of bacteria for sensitivity to existing phage are provided.

Modification ANasopharyngeal and pneumococcal applications phage solutions for nebulization

The application of the bacteriophage can be performed in various ways. The three main approaches are:

1. the phage solution was atomized by a ventilator using a phage atomizer.

2. Atomizing the phage solution by

a. Pressurized gas metering inhaler

b. Atomization

b1. Spray atomizer

b2. A membrane atomizer.

3. Pulmonary application is performed by a powder inhaler.

-selecting 1:

phage atomization by a ventilator uses a phage atomization device which is mounted as an intermediate member to a ventilation hose and connected downstream of a ventilation filter. A flutter valve (flutter valve) allows BPH to be carried while the patient is ventilating. Due to the set ventilation pressure, the same amount of phage solution was always applied at each ventilation. The vibrating valve is closed by reversing the pressure during exhalation, so that no phage solution is delivered during exhalation. A mesh is located between the BPH solution and the vibrating valve, the mesh defining the size of the atomized droplets. Different meshes may be provided for different treatment targets and BPH target areas, resulting in different droplet sizes.

Since the use of the phage atomization device does not interfere with the airflow, CO ₂ The measurement and nebulization of other therapeutic agents may be unlimited.

-selecting 2:

the phage solution is stored in a container suitable for a pressurized gas aerosol. The mode of operation is similar to commonly known pressurized gas aerosols.

In other nebulizer embodiments, the phage solution is packaged as a single dose of stable solution and inserted into a suitable device prior to inhalation.

Therapeutic doses of phage can be inhaled in an environmentally isolated manner by all of the above modes of application. The solution is atomized to droplet size < 5 microns, reaching the bronchial tree up to the alveoli by appropriate inhalation.

-selecting 3:

the phage is applied to a carrier material (e.g. lactose) and can be used in bulk or as a single dose (capsule, blister, etc.) for appropriate inhalation. The operation of the inhalation device is similar to the powder inhalers on the market, as follows:

the device mechanism is used to pierce the capsule, blister, etc., thereby releasing the powder. By vigorous inhalation by the patient, the powder is swirled in the device by the obstruction and then inhaled with the air flow.

-spray drying

A suitable carrier material (e.g. lactose) is dissolved in the phage solution. The solution was reconverted to a solid aggregate state by spray drying. This results in a solid, amorphous state of the support material. This state results in immediate dissolution of the material in the extracellular fluid, with concomitant release of the phage.

Spraying the phages onto a suitable carrier material

Another second option for applying a suitable phage solution to the respective carrier material is spraying, wherein the carrier material is moved and transported under the nozzle spraying the phage solution. It is important that the carrier material flows to obtain uniform wetting from all sides.

Modification B-in vivo use:

1) sterile phage gel (modified release).

The sterile phage gel can be applied in vivo in all places. It was prepared from the appropriate phage solution:

the gel is prepared and sterilized by a gel aid (e.g., HPMC, etc.), without any added moisture, and will be subsequently added as a phage solution. Adhesive substances may be added to improve adhesion to different materials (PTFE, ceramic, dacron, titanium … …). The phage solution was sterile filtered under sterile conditions and maintained sterile in a syringe. The sterilized gel was also stored in a syringe under sterile conditions. For better storage, the surgical team mixes the two components by a double syringe technique shortly before application.

The characteristics of the resulting gel, and thus the rate of phage release, are defined by the amount of gel aid used. Thus, a different gel matrix should remain in the syringe. All phage solutions with different phage compositions can be combined with all gel matrices using the double syringe technique.

Thus, the surgeon can decide during surgery which viscosity/release to apply and which phage composition. The release is fast in low viscosity gels and longer in high viscosity phage gels. The individual syringes (for the gel matrix and phage solution) are aseptically packaged and delivered to non-sterile surgical personnel in a sterile state as required. Sterile operating room personnel mix the components over a predetermined period of time using a dual syringe technique. The phage gel is now ready for use.

Other manufacturing options:

using mechanical production, the phage solution is mixed with the initial part of the gel and sterile filtered. This conditioning of the base gel is achieved by appropriate mixing of the gel aids under sterile conditions in downstream production steps;

mechanical sterile filling of phage solution and base gel. The base gel is then sterilized in the final container. The combination is flexibly accomplished, similar to the initial manual procedure described above.

Additional selection of sterile phage gels:

A. the phage are distributed in the hydrogel matrix in a uniformly embedded manner. The release from the hydrogel will be determined by the ratio of hydrogel adjuvant to the ratio of water. The product has no interaction with skin or mucosa cells, is inert to human body, and can be used in vivo and in vitro; possible gel aids include carbomer (carbomer), cellulose ethers, gelatin, alginates, betanides, highly dispersed silica.

B. The phage are embedded in a lipophilic gel matrix. The release from the hydrogel will be determined by the ratio of lipophilic gelling agent to water. In addition to the antibacterial mechanism, the product is highly moisture retaining, supports the natural wound healing process and antibacterial treatment/prevention. It is particularly suitable for use in vitro, in particular on the skin;

possible lipophilic gelling agents are highly dispersed silicas, aluminum soaps, zinc soaps, in particular each with a suitable lipophilic salt group, for example mineral oils or liquid triglycerides.

C. The phage are embedded in an amphiphilic gel matrix. The release from the hydrogel will be determined by the ratio of amphiphilic gelling agent to water. The product can be used in vitro (see "b."). In particular for further processing.

All gels can also be introduced by syringe in a minimally invasive manner. Thus, percutaneous applications (e.g., into abscesses) are also possible.

2) Aseptic phage soft capsule

First, a gel was prepared as described above. The difference here is that the final product, i.e. "final gel", is prepared. Such gels, which can freely vary in viscosity, BPH content and BPH composition, are then aseptically filled into soft capsules using a rotary die process (rotary die process), a dropping process (dropping process) or other suitable technical process for the production of soft capsules. For example, gelatin is used as the encapsulating material. The capsule material is selected according to the requirement. Appropriate requirements may be release rate and therapeutic range. What is meant herein is that in the presence of body fluids and body temperature, the lower viscosity forms liquefy faster and more strongly, and thus these forms of exudate from the application site are stronger and span a larger area. If the BPH formulation is more likely to remain at the application site, a higher viscosity form should be used that is less prone to rapid liquefaction by body temperature and body fluids, and thus remains at the application site for a longer period of time. Furthermore, the thickness of the capsule shell and the size of the capsule itself can be varied by the process.

3) Sterile soft capsule chain

As described above, the soft capsules were produced as required. After proper manufacture, the capsules are mounted on a monofilament, hydrolytically degradable thread with a fixed distance between them. This allows for application during surgery, even in body cavities. The capsules are mounted on non-degradable material for applications having, for example, wicking.

4) Aseptic bacteriophage sponge

Gels have been proposed as a basis. They will be freeze-dried (= lyophilized) under precise adjustment and control of the influencing parameters as well as under sterile conditions. Furthermore, any dry choice for the application of producing solid phages from a suitable gel is possible.

a. After freeze-drying, the phage are embedded in a solid matrix. The release occurs in a radial manner, i.e. from the outside to the inside, corresponding to a slow release mechanism. The release will be determined by the ratio of the gelling aid to the water.

b. The phage are embedded in the now solid lipophilic gel matrix. The release is radial, i.e. from the outside to the inside, corresponding to a slow release mechanism. The release will be determined by the ratio of the gelling aid to the water.

c. The phage are embedded in the now solid amphiphilic gel matrix. The release is radial, i.e. from the outside to the inside, corresponding to a slow release mechanism. The release will be determined by the ratio of the gelling aid to the water.

Such galenic formulations lead to a sustained release of the antibiotic agent. The release rate will be determined by the surface area to volume ratio. In addition, collagen fibers may be added to the starting gel to support a suitable gel matrix as a stabilizer.

Modification CDermal phage application/wound dressing

Sterile bacteriophage powder

Phage products (e.g., phage powder for inhalation) are produced aseptically and stored in tightly sealed outer packaging to prevent moisture. The product is particularly suitable for exuding wounds, such as burns.

Sterile phage sponges as wound dressings

Suitable for use with the phage sponges explained above. Which is covered with an adhesive matrix/adhesive layer having a size exceeding that of the sponge. These adhesive edges (consisting for example of polyacrylamide as adhesive component) serve as a conditioning mechanism on healthy skin.

Deformed D-phage suture material

For example, in suture manufacturing, the monofilament suture material after manufacturing may be reheated to a maximum temperature of 35 ℃ to loosen the suture material, and upon further heating, the suture is sprayed with phage solution or phage gel in circulation, and then the phage solution is absorbed during cooling.

In the case of a multifilament suture material (i.e. a suture material consisting of more than one filament), no heat is applied, but only the phage solution or phage gel is sprayed, as the solution or gel settles to the contact areas of the individual filaments, leaving behind on the suture material under the subsequent cooling action.

Regardless of the manufacturing, any suture material may also be placed and packaged in a suitable gel, such that the gel surrounds the filament throughout storage.

In particular in the case of hydrolytically cleavable suture materials, special care must be taken to ensure that the gel contains a lipophilic gelling aid and that the phage used for gel generation is present in the W/O emulsion. The phage solution provides water that is captured by the oil. This W/O build-up can be carried out with the aid of micelles or emulsifiers.

In the following, examples of technical implementation of phage application will be provided. They are based on the route of application. The aim of all proposed phage applications is to introduce therapeutically active phage for the prevention and/or minimization of bacterial infections. In addition, techniques are provided to facilitate phage recovery, stabilize or test bacteria for susceptibility to existing phage.

In the description of the drawings, exemplary embodiments of the invention will be described in detail with reference to the accompanying drawings, in which additional embodiments not shown in the drawings will be shown below. These embodiments are illustrative of the invention and are not intended to be limiting.

In the drawings:

FIG. 1 is a schematic diagram of one embodiment of a first phage application apparatus;

FIG. 2 is a schematic diagram of one embodiment of a second bacteriophage application device;

figure 3 shows a hard capsule appropriately filled with phage and carrier material and designed for proper handling of the device;

FIG. 4 is another application variation, wherein in vivo phage application is shown herein;

FIG. 5 shows another application, in which a sterile phage softgel application is depicted;

FIG. 6 shows phage soft capsule chain application;

FIG. 7 shows a phage sponge-gel application variant;

FIG. 8 is a schematic diagram of one embodiment of a phage sensitivity test application shown in an initial state; and

FIG. 9 is a schematic diagram of an exemplary embodiment of the phage sensitivity test application of FIG. 9 at a testing stage.

Fig. 1 is a schematic diagram of an exemplary embodiment of a first application, wherein the application of bacteriophage for the lungs and respiratory tract is shown, wherein the bacteriophage solution for nebulization is provided by means of a bacteriophage application device.

In this regard, the bacteriophage application is performed using several types of bacteriophage application devices that are either directly proximate to the airway of the user or that are connectable to existing breath supply devices.

The first bacteriophage application device comprises a pressurised gas metering aerosol chamber through which the bacteriophage solution may be connected to a breathing device. The phage solution was stored in a container matched to the pressurized gas aerosol.

Figure 2 shows a second bacteriophage application device comprising an aerosolization chamber through which the bacteriophage solution may be connected to a respiratory device, the aerosolization chamber having a jet nebulizer and/or a membrane nebulizer.

Phage nebulization by ventilator using a phage nebulizing device installed as an intermediate component in the breathing tube and connected downstream of the breathing filter. During ventilation of the patient, the phage is carried through the vibrating valve. Due to the set aeration pressure, the same amount of BPH solution is always applied per aeration. The vibrating valve is closed by reversing the pressure during exhalation, so that the phage solution is not delivered during exhalation. Between the BPH solution and the vibrating valve is a mesh that sets the size of the atomized droplets. Different networks can be provided for different treatment targets and phage target areas, so that different droplet sizes can be generated. Since the phage atomizer does not interfere with the airflow, CO ₂ Nebulization of measurement and other therapeutic agents remains unlimited. The phage solution is preferably packaged as a stable solution in a single dose and added to a suitable device prior to inhalation.

Another type of bacteriophage application device (not shown) has a powder inhaler. The phage is applied to a carrier material and held in bulk or as a single dose (capsule, blister, etc.) for proper inhalation. An inhalable powder inhaler uses spray drying to dissolve a suitable carrier material (e.g. lactose) in the phage solution. The solution is reconverted to a solid aggregate state by spray drying, resulting in a solid, amorphous carrier material state. This state results in immediate lysis of the material by the extracellular fluid and concomitant release of the phage.

Another method of applying a suitable phage solution to the respective carrier material is by a spraying method, in which the carrier material is placed under a nozzle spraying the phage solution. It is particularly advantageous for the support material to flow to cause overall wetting.

All of the above described applications of bacteriophage can be used to inhale therapeutic doses of environmentally isolated phage. The solution is atomized, in particular, to a droplet size of less than 5 microns, reaching the bronchial tree up to the alveoli by suitable inhalation.

Figure 3 shows a hard capsule appropriately filled with phage and carrier material and designed for proper handling of the device.

FIG. 4 shows another application variation, in which an in vivo phage application to generate a sterile phage gel from a phage solution is shown, which can be applied at all locations in the body using a phage application device.

During the manufacturing process, the gel is prepared using a gelling aid (e.g., HPMC, etc.), without any water portion of the subsequent phage solution, and will be sterilized. Adhesive substances may be added to improve adhesion to different materials (PTFE, ceramic, dacron, titanium, zinc oxide, etc.).

The phage solution is sterile filtered and maintained sterile under sterile conditions, for example in a syringe. The sterile gel is maintained under sterile conditions, for example in a syringe. For better storage, the two components are mixed in time, not earlier than before application, using the double syringe technique.

The characteristics of the resulting gel, and thus the rate of phage release, are defined by the amount of gel aid used. For this purpose, different gel matrices are stored, for example in syringes. All phage solutions with different phage compositions can be combined with all gel matrices using the double syringe technique.

Other ways of providing a gel, e.g. a stepwise process, where automated production is used, e.g. mixing a phage solution with a first part of a gel and sterile filtering, followed by conditioning the base gel in a downstream production step by appropriate mixing of gel aids under sterile conditions.

In addition, the BPH solution and base gel may be automatically aseptically filled, and then the base gel in the final container sterilized. Contact of the BPH with the base gel can then be made as desired.

Alternatively, the BPH solution and base gel may be aseptically filled by machine and the base gel in the final container then sterilized. Contact of the BPH with the base gel can then be made as desired.

Other methods of providing a sterile phage gel include uniformly distributing the phage in a hydrogel matrix. The release from the hydrogel is determined by the ratio of hydrogel adjuvant to the ratio of water. The product does not interact with skin or mucosal cells, will be incorporated into the human organism, and can be used in vivo and in vitro, or the phage can be embedded in a lipophilic gel matrix. The release from the hydrogel will be determined by the ratio of lipophilic gelling agent to water. In addition to the antibacterial mechanism, the product is highly moisture-retaining, supporting the intrinsic wound healing process in addition to antibacterial therapy/prophylaxis. It can be applied in vitro, in particular to the skin, or the bacteriophage can be embedded in an amphiphilic gel matrix. In this case, the release from the hydrogel will be determined by the ratio of amphiphilic coagulant aid to water. The product can also be used in vitro.

The viscosity, release rate and BPH composition can be adjusted immediately prior to application. The release is fast in low viscosity gels and longer in high viscosity BPH gels.

Figure 5 shows another application, in which a sterile phage soft capsule application is shown, in which a gel is initially produced, which, in contrast to the previously described gels, is already provided as the final product of the gel, i.e. no further production steps are required. Such gels, whose viscosity, BPH content and BPH composition can be varied as desired, are aseptically filled into soft capsules using a rotary die process, a drop process or other techniques suitable for producing soft capsules. For example, gelatin is used as a capsule material. The capsule material is selected according to the requirement. Appropriate requirements may be release rate and therapeutic range. What is meant herein is that due to body fluids and body temperature, the low viscosity forms liquefy faster and more strongly, e.g., so that these forms of exudate from the application site are stronger and span a larger area. If the BPH formulation is more likely to remain at the application site, a higher viscosity form should be used that is less prone to rapid liquefaction by body temperature and body fluids and remains at the application site for a longer period of time.

Furthermore, capsule shells of different thicknesses and capsules of different sizes themselves may be used in this process.

Thus, the phage softgel application provides a phage library as a unit, wherein at least one phage is provided as a phage application that maintains stability after being introduced into the body in a determinable time manner.

In addition to the previous embodiments, FIG. 6 illustrates another application in which a sterile bacteriophage softgel capsule chain application is provided. As in the phage soft capsule application, soft capsules were prepared according to the appropriate requirements. After proper manufacture, the capsules are mounted at a fixed distance from each other, in particular on a monofilament hydrolytically degradable thread. This allows for application during surgery, even in body cavities.

Figure 7 shows a morphed phage sponge gel application. Another application shows the application of a sterile phage sponge gel based on an already displayed gel. They are freeze-dried/lyophilized under precise adjustment and control of the influencing parameters and under sterile conditions. Furthermore, all dry options for the application of generating solid phages from suitable gels are allowed.

The phage may be provided as a phage sponge gel application after freeze-drying in a form embedded in a solid matrix, embedded in a now solid lipophilic gel matrix, or embedded in a now solid lipophilic gel matrix. In each case, the release is radial-from the outside to the inside. This corresponds to a slow release mechanism. The release will be determined by the ratio of gel aid to water.

Such galenic formulations lead to a sustained release of the antibiotic agent. The release rate will be determined by the surface area to volume ratio. In addition, collagen fibers may be added to the starting gel to support the corresponding gel matrix as a stabilizer.

FIGS. 8 and 9 show a phage susceptibility test application in which the container is filled with the appropriate phage, bacterial nutrient solution (liquid) and dye that interacts with the bacterial cell wall. Upon interaction, the dye is visible a./the dye is colorless B. A sample, such as a swab (the sampler being included in the kit), is placed directly into the container as the test sample. The dye interacts with the bacteria and is a. The test was incubated at 36 ℃ for 12 to 24 hours. After this time, the sensitivity of the bacteria to the presence of BPH is expressed as a low intensity staining a./b.

Other applications are as follows:

this list of phage applications is not exhaustive. Combinations of phage applications can also be provided, and the material can be coated with phage applications prior to use, resulting in further applications.

One particularly noteworthy exemplary application for the use of specific bacteriophages is prosthetics.

Even today, prosthetic infections are one of the most serious complications of reconstructive surgery. Infection of the prosthesis, especially of the aorta, is affected, often with fatal consequences; this technical field, in particular, is not only highly complex, but is also particularly susceptible to complications due to the large number of plastic prostheses used.

Claims

1. An in vivo phage preparation formed as:

-a sterile bacteriophage gel, wherein the gel is release-regulated; or

-a sterile bacteriophage soft capsule comprising a gel; or

-a sterile softgel chain comprising phage softgels with gels on monofilament hydrolytically degradable filaments or on non-degradable materials; or

-a sterile phage sponge, wherein said sponge is sprayed with a phage solution or phage gel, or the phage gel is freeze-dried.

2. A nasopharyngeal and pulmonary phage preparation, wherein said phage preparation is formed as: a phage solution or a phage powder, wherein the phage preparation is nebulized using at least one of the following variants:

-nebulization by a ventilator using a phage nebulization device;

nebulization by means of a pressurized gas metering aerosol;

atomization by means of a jet atomizer;

-atomization by means of a membrane atomizer;

nebulization by powder inhalers.

3. A dermal phage preparation, wherein the phage preparation is formed as:

sterile phage powder, or

-a sterile phage sponge as wound dressing comprising a phage gel or phage powder.

4. A phage suture preparation characterized in that,

the monofilament suture material is sprayed cyclically with a phage solution or a phage gel, or

-the multifilament suture material is wetted with a phage solution or phage gel, wherein the solution or gel is provided on the suture material and/or in the contact area.

5. A two-syringe phage preparation, characterized in that a first syringe is prepared with a phage solution and a second syringe is prepared with a gel, the two syringes being connectable to each other, wherein mixing of the gel with the phage solution is possible, and the mixture is then present in the syringe ready for use.

6. The dual syringe phage preparation of the preceding claim, wherein different gels and/or different phage solutions are stored for different combinations from each other and mixed with each other accordingly to form dedicated phage solution gels.

7. A nasopharyngeal and pulmonary phage preparation apparatus, wherein phage solution or phage powder is atomized using at least one of the following means, and the phage atomization means is formed as:

-a ventilator comprising an aerosolization device or a pressurized gas dose aerosol chamber;

-a pressurised gas metering aerosol;

-a container inhalation device comprising an nebulization chamber and a jet nebulizer or a membrane nebulizer;

-an inhaler device comprising a pressurised gas metered dose inhaler;

-a powder inhaler.

8. Use of a bacteriophage sensitivity test, characterized in that the bacteriophage, a bacterial nutrient solution and a dye are placed in a container, wherein the dye is capable of interacting with the bacterial cell wall.